Huntington's disease (HD) presently lacks any effective therapy. Our goal is to evaluate neuronal replacement as a novel treatment strategy for HD and to provide relevant information for understanding the pathophysiology of HD. Previous experiments involved animals with unilateral caudate- putamen lesions. We will now realistically test for beneficial effects in a clinically relevant animal model by transplanting xenogeneic neurons bilaterally into the neuron-depleted posterior putamen, a region that is bilaterally and severely involved in the HD motor-disorder. Neuronal loss remarkably similar to HD is produced in macaca mulata by MRI-guided bilateral quinolinate (200 mM) infusion into posterior putamen. A quantifiable movement disorder analogous to HD occurs after dopamine- agonist drug stimulation (apomorphine 0.5 mg/kg i.m., 40 min. test). We will determine how porcine striatal neuroblasts repair this putaminal neurocircuitry and consistently reduce the movement disorder: First, during behavioral recovery, we obtain specific and complementary in vivo data about neuronal function through MRI techniques, scanning of striatal neurons (dopamine D1; SCH 39166 binding) and 2-deoxyglucose utilization using PET. Second, post-mortem studies using species-specific markers for neuronal circuitry and neurochemical analysis of neurotransmitter changes will demonstrate how transplanted cells integrate with the host brain. Third, by immunologically rejecting functional transplants, we will test host dependency on transplanted neurons. Our ongoing work shows that implanted embryonic porcine striatal neurons can compensate in part for lesion-induced neurological deficits in a primate model of HD. The novel work proposed may provide a rational basis for clinical trials in HD.